# US 10,865,217 B2 · Process for the preparation of 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-[2,1]-benzoxaborole and polymorphs thereof

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- Number: US 10,865,217 B2
- Document ID: US10865217B2
- Status: Granted
- Kind: B2
- Application number: 16/616,030
- Filed: 2018-05-23
- Published: 2020-06-18
- Granted: 2020-12-15
- Earliest claimed: 2017-05-23
- Assignees: Msn Laboratories Private Limited, R&D Center
- Applicants: Msn Laboratories Private Limited, R&D Center; Thirumalai Rajan Srinivasan
- Inventors: Thirumalai Rajan Srinivasan; Eswaraiah Sajja; Venkat Reddy Ghojala; Markandeya Bekkam
- Web page: https://patentgrep.com/patent/US10865217B2

## CPC

- A61K 31/69: Boron compounds
- C07F 5/027: {Organoboranes and organoborohydrides}
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to process for the preparation of 5-(4-cyano phenoxy)-1,3-dihydro-1-hydroxy-[2,1]-benzoxaborole represented by the following structural formula-1 and polymorphs thereof. The present invention also relates to salts of 5-(4-cyano phenoxy)-1,3-dihydro-1-hydroxy-[2,1]-benzoxaborole and process for their preparation and their use in the preparation of pure compound of the formula-1.

## Claims

### Claim 1

A process for the preparation of 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-[2,1]-benzoxaborole compound of formula-1, comprising;
a) reacting 2-halo-5-hydroxybenzyl acetate compound of general formula-4
with 4-halobenzonitrile compound of general formula-5
wherein, ‘X’ represents halogens such as F, Cl, Br & I;
to obtain 2-halo-5-(4-cyanophenoxy)benzyl acetate compound of general formula-6, and
b) converting the compound of general formula-6 into compound of formula-1.

### Claim 2 (depends on 1)

The process according to claim 1, comprising reacting compound of general formula-6 with bis(pinacolato)diboron compound having the following formula
in presence of a palladium catalyst and a base in a solvent to provide 5-(4-cyanophenoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate compound of formula-7,
and treating compound of formula-7 with an acid optionally in presence of a solvent to provide compound of formula-1.

### Claim 3 (depends on 1)

The process according to claim 1, wherein,
the reaction in step-a) is carried out in presence of a base selected from inorganic bases, organic bases or mixtures thereof in a solvent selected from the group consisting of hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, and mixtures thereof.

### Claim 4 (depends on 2)

The process according to claim 2, wherein
the palladium catalyst is selected from the group consisting of palladium(II) acetate, palladium(II) acetoacetonate, palladium chloride (PdCl2), tetrakis(triphenyl phosphine)palladium, dichlorobis(triphenylphosphine)palladium, [1,1′-bis(diphenylphosphino) ferrocene] dichloro palladium(II) [Pd(dppf)Cl2], and combinations thereof; and
wherein the reaction can be carried out optionally in presence of a ligand such as triphenylphosphine, tri(o-tolyl)phosphine, tricyclohexylphosphine combinations thereof;
a base is selected from inorganic bases, organic bases or mixtures thereof;
an acid is preferably hydrochloric acid; and
a solvent is selected from the group consisting of hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, and mixtures thereof.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the 2-halo-5-hydroxybenzyl acetate compound of general formula-4
wherein, ‘X’ represents halogens such as F, Cl, Br & I;
is prepared by reacting 4-halo-3-(hydroxymethyl)phenol compound of general formula-3
with an acetylating agent, optionally in presence of a base in a solvent.

### Claim 6 (depends on 5)

The process according to claim 5, wherein
the acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride, acetic acid and mixtures thereof; the base is selected from organic bases; and
the solvent is selected from the group consisting of hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, and mixtures thereof.

### Claim 7 (depends on 2)

The process according to claim 2 further comprising purification of compound of formula-1, comprising:
a) reacting the compound of formula-1 with an organic amine in a solvent,
b) optionally isolating the organic amine salt of compound of formula-1 from the reaction mixture, and
c) treating the organic amine salt of compound of formula-1 with an acid optionally in presence of a solvent to provide pure compound of formula-1.

### Claim 8 (depends on 7)

The process according to claim 7, wherein,
the “organic amine” is selected from methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, iso-butyl amine, tertiary butyl amine, octyl amine, 2-ethyl hexylamine, benzyl amine, α-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentyl amine, cyclohexyl amine, cycloheptylamine, N-methylcyclopentylamine, N-ethyl cyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexyl amine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like;
the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, p-toluene sulfonic acid, methane sulfonic acid, trifluoroacetic acid and the like;
the solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents and the like or mixtures thereof.

### Claim 9 (depends on 7)

The process according to claim 7, wherein the organic amine salt is preferably tertiary butyl amine salt.

### Claim 10 (depends on 9)

The process according to claim 9, wherein the tertiary butyl amine salt of compound of formula-1 is obtained as a crystalline solid.